Pharmacologic profiling of transcriptional targets deciphers promoter logic.
- Resource Type
- Article
- Authors
- Freebern, W. J.; Haggerty, C. M.; Montano, I.; McNutt, M. C.; Collins, I.; Graham, A.; Chandramouli, G. V. R.; Stewart, D. H.; Biebuyck, H. A.; Taub, D. D.; Gardner, K.
- Source
- Pharmacogenomics Journal. 2005, Vol. 5 Issue 5, p305-323. 19p. 9 Diagrams, 2 Charts, 4 Graphs.
- Subject
- *GENETIC transcription
*CELLULAR signal transduction
*BIOENERGETICS
*MULTIVARIATE analysis
*CYCLOSPORINE
*CYCLIC peptides
- Language
- ISSN
- 1470-269X
The blueprint for cellular diversity and response to environmental change is encoded in the cis-acting regulatory sequences of most genes. Deciphering this ‘cis-regulatory code’ requires multivariate data sets that examine how these regions coordinate transcription in response to diverse environmental stimuli and therapeutic treatments. We describe a transcriptional approach that profiles the activation of multiple transcriptional targets against combinatorial arrays of therapeutic and signal transducing agents. Application of this approach demonstrates how cis-element composition and promoter context combine to influence transcription downstream of mitogen-induced signaling networks. Computational dissection of these transcriptional profiles in activated T cells uncovers a novel regulatory synergy between IGF-1 and CD28 costimulation that modulates NF-κB and AP1 pathways through signaling cascades sensitive to cyclosporin A and wortmannin. This approach provides a broader view of the hierarchical signal integration governing gene expression and will facilitate a practical design of combinatorial therapeutic strategies for exploiting critical control points in transcriptional regulation.The Pharmacogenomics Journal (2005) 5, 305–323. doi:10.1038/sj.tpj.6500325; published online 26 July 2005 [ABSTRACT FROM AUTHOR]